[unreadable] To date, few studies have directly examined the effect of long-term morphine use on tumor growth. It is well documented that vascular endothelial growth factor is a crucial factor in vascular angiogenesis and tumor growth. Furthermore, macrophages that infiltrate to the tumor site are more potent inducers of angiogenesis. Our preliminary data indicate that chronic morphine treatment suppresses tumor growth by significantly inhibiting tumor angiogenesis increasing tumor cell apoptosis and decreasing activated macrophage infiltration into the tumor site. The major focus of this research plan is to initially investigate the mechanisms by which morphine mediates these effects. In specific Aim 1: We will investigate the mechanism by which morphine modulates prolyl hydroxylases levels to alter hypoxia inducible transcription factors to reduce tumor cell secretion of VEGF and suppress tumor cell-induced angiogenesis and tumor growth. In Specific Aim 2: We will determine if morphine suppresses tumor cell production of monocyte chemoattractant protein to reduce the migration of blood monocytes and or CC receptor 2 expressions for macrophage activation for infiltration into the tumor microenvironment to promote and further sustain tumor angiogenesis. [unreadable] [unreadable] [unreadable] [unreadable]